Ep.250: Dr. Raphael Mechoulam

Ep.250: Dr. Raphael Mechoulam

The Copernicus of Cannabis, Dr. Raphael Mechoulam joins us to discuss the advent of cannabis research, it’s history and current landscape. He says it’s very difficult to work on compounds, that are under legal constraints. When he started there was some knowledge around cannabinoids but it was vague and not in modern terms. As a natural products chemist he knew that the first thing that needed to be done was to elucidate the chemistry as you can’t do research with an unknown extract. He read historical information on the plant in many different languages to set his baseline understanding. This eventually set him up to be the custodian of the world’s supply of legal THC in 1963 which at the time was 10 grams and the rest as they say, is history.

Transcript:

Speaker 1: The Copernicus of cannabis. In celebration of episode 2:50, Dr Raphael Mechoulam joins us to discuss the advent of cannabis research. It's history and current landscape. He says it's very difficult to work on compounds that are under legal constraints. When he started, there was some knowledge around cannabinoids, but it was vague and not in modern terms. As a natural product chemist, he knew that the first thing that needed to be done was to elucidate the chemistry. As you can't do research with an unknown extract, he read historical information on the planet in many different languages. To set his baseline understanding, this eventually set them up to be the custodian of the world's supply of legal thc. In 1963, which at the time was 10 grams. Walk into cannabis economy. I'm your host Seth Adler. Check us out on social with the habit can economy. That's two ends of the word economy. Rafi Michelen. So here we are. We're in Hebrew University.

Speaker 2: So Eh, when I started working on cannabis was many years ago, it was one of the projects that we stopped at that that time I started. I'm a natural product chemist. I work in natural products and compounds that are found in plants or an animal that basically compounds that are found in plants because every family of plants has different types of chemicals at times. Not always different types of chemicals. The no, the, the family supplant. So the thousands, many hundreds of thousands of compounds and many of them have been used as a medicine for, for ages and others we don't know the structure. We don't know what did they work. And one of the blonde side decided to work on what's kind of the. That's my kind of first question. And uh, Dr Michelle dot Professor Rafi. Thank you for having me. And this is an honor. It's a pleasure.

Speaker 3: Um, how did you. Yes. You. Okay. You're working with, uh, the, you know, with plant medicine, but what are we talking about? Nineteen 60. What are we talking? The three. How did you come to cannabis? No one is looking at cannabis at that time. Right. How did you find cannabis? Well, the story's complicated. You see, morphine had been isolated from opium, a 150 years previously and cocaine had been discovered in the 19th century from coca leaves seem strange. Did the active compound had never of cannabis had never been isolated in pure form, although in the thirties and early forties, some very good groups and worked than that in, in the US. Roger, Adam, so well known chemists in the UK, a lot toward in Oxford had worked on that and got a Nobel prize, done something else, but then work stopped and for various reasons, some of them are legal.

Speaker 3: It is very difficult to work with compounds, do research and compounds that are under legal constraints. Indeed. And I mean universities in open, open place, the lab people come in, students come in, students go out, you cannot have a, uh, a policeman standing in front of the door and so on. So essentially when we started work, there were very, very few groups. There was one in Germany that was working a little bit and that was about it. So, uh, Eh, there, there was some no lich under chemistry of cannabinoids, but it was vague and not on the modern terms. And uh, when we started work, Eh, I knew as a natural product chemist that first we have to elucidate the chemistry and the reason for that is you cannot do research with and they extract that. You don't know what it's in there. That's not modern science.

Speaker 3: You'll have to have a identified compounds, pure compounds. Do you know what you're giving to the mouse or rat? I thought it's a good idea to go ahead and, uh, uh, we got cannabis from the police. This is a, I want you to tell the story of the bus. But before, as far as you know, finding cannabis, was it because you were studying natural products and you had heard about cannabis through your discovery of other plant medicine? Is that basically it? Well, no, it's a little bit more than that. A cannabis of course had been known knowns. The research had been done on it. It was, there was no more reach in the thirties and forties. But, uh, there was, and there were a lot of, uh, uh, publications, old publications, the describe the cannabis as a treatment is cannabis as a recreational drug. Cannabis in many, many different forms.

Speaker 1: The Copernicus of cannabis. In celebration of episode 2:50, Dr Raphael Mechoulam joins us to discuss the advent of cannabis research. It's history and current landscape. He says it's very difficult to work on compounds that are under legal constraints. When he started, there was some knowledge around cannabinoids, but it was vague and not in modern terms. As a natural product chemist, he knew that the first thing that needed to be done was to elucidate the chemistry. As you can't do research with an unknown extract, he read historical information on the planet in many different languages. To set his baseline understanding, this eventually set them up to be the custodian of the world's supply of legal thc. In 1963, which at the time was 10 grams. Walk into cannabis economy. I'm your host Seth Adler. Check us out on social with the habit can economy. That's two ends of the word economy. Rafi Michelen. So here we are. We're in Hebrew University.

Speaker 2: So Eh, when I started working on cannabis was many years ago, it was one of the projects that we stopped at that that time I started. I'm a natural product chemist. I work in natural products and compounds that are found in plants or an animal that basically compounds that are found in plants because every family of plants has different types of chemicals at times. Not always different types of chemicals. The no, the, the family supplant. So the thousands, many hundreds of thousands of compounds and many of them have been used as a medicine for, for ages and others we don't know the structure. We don't know what did they work. And one of the blonde side decided to work on what's kind of the. That's my kind of first question. And uh, Dr Michelle dot Professor Rafi. Thank you for having me. And this is an honor. It's a pleasure.

Speaker 3: Um, how did you. Yes. You. Okay. You're working with, uh, the, you know, with plant medicine, but what are we talking about? Nineteen 60. What are we talking? The three. How did you come to cannabis? No one is looking at cannabis at that time. Right. How did you find cannabis? Well, the story's complicated. You see, morphine had been isolated from opium, a 150 years previously and cocaine had been discovered in the 19th century from coca leaves seem strange. Did the active compound had never of cannabis had never been isolated in pure form, although in the thirties and early forties, some very good groups and worked than that in, in the US. Roger, Adam, so well known chemists in the UK, a lot toward in Oxford had worked on that and got a Nobel prize, done something else, but then work stopped and for various reasons, some of them are legal.

Speaker 3: It is very difficult to work with compounds, do research and compounds that are under legal constraints. Indeed. And I mean universities in open, open place, the lab people come in, students come in, students go out, you cannot have a, uh, a policeman standing in front of the door and so on. So essentially when we started work, there were very, very few groups. There was one in Germany that was working a little bit and that was about it. So, uh, Eh, there, there was some no lich under chemistry of cannabinoids, but it was vague and not on the modern terms. And uh, when we started work, Eh, I knew as a natural product chemist that first we have to elucidate the chemistry and the reason for that is you cannot do research with and they extract that. You don't know what it's in there. That's not modern science.

Speaker 3: You'll have to have a identified compounds, pure compounds. Do you know what you're giving to the mouse or rat? I thought it's a good idea to go ahead and, uh, uh, we got cannabis from the police. This is a, I want you to tell the story of the bus. But before, as far as you know, finding cannabis, was it because you were studying natural products and you had heard about cannabis through your discovery of other plant medicine? Is that basically it? Well, no, it's a little bit more than that. A cannabis of course had been known knowns. The research had been done on it. It was, there was no more reach in the thirties and forties. But, uh, there was, and there were a lot of, uh, uh, publications, old publications, the describe the cannabis as a treatment is cannabis as a recreational drug. Cannabis in many, many different forms.

Speaker 3: This was in various languages. It was ingression in French, in German. But, um, I knew most of these languages. See, I come from a small country and my parents insisted that, well, you better know more than just Bulgarian, not too many people in this damn world, Nobel guerin so you better know English and German and French and the Russian. So, so I knew most of these languages and I could read the papers and they seem very interesting. So I thought it's a good idea to go ahead and try to identify what it's whatever is it in India. And I got a, I actually asked for a grant from Nih and they told me that time that it's a cannabis is not relevant to what's going on in the US. Nobody smokes except some, they told me orally. Oh, some black musician smoking the jasmine. Exactly right.

Speaker 3: And nobody else does some of the Mexican farmers out west. Right. That's a whole different story, right? So when you have something more relevant contact. Yeah. Okay. Actually, they came back to me a year later. All of a sudden cannabis became relevant because of the son of a, somebody important or maybe a senator was caught smoking pot and he wanted to know whether it's destroying his brain and they didn't have a single grant on that. Nih. And they came over and uh, by that time we had isolated the active constituent and we knew quite a lot about it. So they took the whole, the world supply of pure thc, which is about 10 grands probably. They took it and they smuggled it back into the US. They probably didn't have a license. They smuggled in. Some of the research done originally was done with the material that was smuggled from here, from here.

Speaker 3: But first let's get you go to the police, right? We, in order to get the material, we had to go to the. I mean, there were the only suppliers. Sure. And the police, they burn it today. They what's going on is, uh, is being grown in the Lebanon and smuggled a from the Lebanon does a apparently a good coordination or, uh, between them, uh, Arabs in the Lebanon and the Jews in Israel on this, uh, in this field. They worked together apparently pretty well. There you go. This does bring people together, doesn't at times the police catches a cannabis which comes in souls. It's a small bags that was smuggled apparently ages ago in shoes. And so they are called SOS. So they used to burn it after a couple of months and when we asked for it, they asked whether I'm reliable and the administration of the Weitzman Institute told him, well, yes, he's reliable.

Speaker 3: They barely, barely knew me. And so I said, okay, come over and pick it up. And I went there and to five kilos of hashish and went on the bus. I didn't have a car at that time. I went down to person. There was a lot of interesting smell. Nobody had done the, had kind of felt that kind of smell and started working in it with, with a colleague of mine. Now what happened was that we had broken the loss because the police was not a. we're not allowed to give me the Kennedys. The Ministry of Health was in the states. Chances are that I would have ended in prison. Yeah, sure. Absolutely. Yeah. Uh, in Israel, I went to the Ministry of Health. I said, I, I'm sorry, you'll pilot. We drank coffee together and uh, I think one of the people there was a student of mine, so want Montes teacher to go to prison, right?

Speaker 3: And said, next time you do it the right way. And I did it the right way whenever I need it over the next few years can be. So I would ask the ministry to give me a, to approve it. I would go there and drink a cup of coffee with them, take the approval, go to the, to, to police, drink a cup of coffee with the police, get the cannabis, go back. And it was completely legal and we didn't have a policeman at the door. Nobody cared for. Once it was out of there and in here, no one cares. Have a few years later, I moved to the Hebrew University. I don't know, maybe the Weizmann Institute. We're not happy with the research I was doing or maybe something else. Anyway, I decided to move. They asked me here to be head of department and I was head of Department of natural products for many years. Before we get to the work here.

Speaker 3: If you could sum up the work that you were doing at Weitzman, maybe they weren't pleased with it but it, but share with us in the mid sixties there. What were you looking at? A two types of work. We first of all had to identify the constituents. We had to find out what the hell is in there. Right. And it turned out that one of the reasons at the chemistry was not well known because there is a huge, huge mixture of closely related compounds today. We know that there are about 100 of them or maybe even more, uh, only two or three major ones. But even so there's a mixture and therefore it was in the thirties. Difficult to separate the material. The techniques were apparently not a well developed, the scientific techniques, techniques to separate materials. So we, eh, my colleague Dr Anya and I worked on that.

Speaker 3: Then we'll able to separate about 10 or 12 compounds. I knew most of them were completely new and uh, one of them we call it kind of be general and other one can be roaming and the third one it's on, so forth. And so these compounds with tested by a group in a biological research institute which about a few kilometers away. And uh, they found that only one of the compounds affected monkeys resists monkeys, uh, affected by cannabis, but only one of the 10 or 15 compounds that we gave them. Only one compound caused them to go to sleep. If you wish, I'll get sedated a otherwise reasons monkeys, a pretty violent. I mean the, I don't suggest to anybody that he should try and play around with the resist monkey, but these reasons monkey well, it kind of slowed down. And uh, but the only wheat thc, thc.

Speaker 3: So on this basis we said this is the only active compound. We elucidated the structure and the stereochemistry the way it's built in space and uh, uh, later synthesize it and it became available in relatively large amount and there was a second compound which is not psycho active, which had been isolated in pure form in the thirties, but the structure was not known and so elucidated the structure and it was a compound called cannabidiol. And this compound was turned out to be of extreme interest because not being psychoactive, but having a lot of medicinal positive medicinal property. So this is cbd, CBD, even folks now that are not in the industry and really don't know much, are starting to hear about cbd. So what would Raffi, how would you describe CBD to those folks? Is present in cannabis, but it does not cause the effects that we know the marijuana effect.

Speaker 3: It is completely inactive in this respect, but it is anti inflammatory. It lowers inflammation. Uh, it, uh, is active in a large series of diseases for various reasons. There are various mechanisms through which it does the job and chances are that it will become a drug. At the moment, it's not yet the drug because of legal, the legal situation in the US surprisingly cannot be dial as it comes from cannabis in the same category as heroin. Um, schedule with a little bit of Cannabidiol, a or a little bit of heritage, the same, which is kind of really ridiculous because cannot be directly, is not toxic, does not cause any side effects and is not psychoactive. So, uh, it can be given at very high doses, uh, as a drug and it has been given the high doses. We a administered cannot be dial to epileptic patients.

Speaker 3: Thirty five years ago. Exactly in, in, uh, in Brazil. My colleagues in Brazil, they did a clinical trial in 15 patients, half of them got placebo, half of them got to 300 milligrams of thc. And it turned out that yes, it was extremely potent. Of course we did before that work on mice. So we knew what to expect. You cannot go directly into a human right. And it was a pretty active. Out of the eight patients that got it for, had almost no seizures anymore. Three had much less than one was not affected, so I thought, oh, here is something that is very promising, and we thought that, uh, uh, people will expand that observation because new epitope antiepileptic drugs are needed. Well, it turned out that, uh, nothing happened until five, six years ago when parents that have epileptic children and nothing was helping them anymore realize by maybe somebody had read the paper, maybe other people had learned from just people that are trying to do something with that children's just experimenting that yes, Cannabidiol, excellent drug without, of course it's not available in Colorado. It, there was as a strain that had a large amount of a large levels of canopy dial. And so people in the US went to Colorado just because of the PR. That strain that's available there. Now that that's a strange story. I mean, if something is active and then first of all, the clinicians should have repeated, expanded this world. We didn't have to wait 35 years. So many children could have been helped or they weren't.

Speaker 4: I can, I can hear your frustration. I can see your frustration. You know what, why? How is that possible that there was that gap? You were the one that you were on top of that research 35 years ago. Is it a. What is the. What was the issue? Thank goodness that we're kind of coming out of that now, but what do you think? It was really difficult to say. Probably the legal site. It was to blame to a certain extent, very difficult to do

Speaker 3: clinical trials or even animal trials, but certainly clinical trials with a drug that's not legal. Right, and even to this very day, there are very few major clinical trials going on in the US. Yes, there is a clinical trial going on with a plant extract that contains very high levels of cbd and it's being done on a large number of patients. It was approved. I understand by the FDA that was under popular pressure. People said, now what's going on here is something that helps. We know it helps and why don't we have clinical trials, so fda approved it. As a matter of fact, in Israel it's approved and the strains we tie cbd that administer to that kind to those children that have Epi, a pediatric epilepsy and it helps in about 60 percent of cases, which is fine. Uh, it should have been done 35 years previously, but there we are at the moment.

Speaker 3: But again, that's it. Um, I can make a list of quite a lot of diseases that can be dialed helps and nothing, right? Nothing in the states or the hearing dale down some experiments being done. Uh, an example, uh, bone marrow replacement of bone marrow is, uh, one of the treatments or certain kinds of cancer. But bone marrow replacement, a bone marrow is not the simple procedure. Now, very complex and dangerous loot bone marrow from the outside, hopefully from a relative, but still the body doesn't, doesn't want it. So the body attacks the bone marrow, the bone marrow attacks the body and the sick. The person that's sick is very sick. But my mother had this done. Yes, very unpleasant. It, it works in many cases is definitely a good procedure, but it's not a simple procedure. It is kind of announced to immune reaction, namely the body attacks itself and we, we and others have shown that this is something that cannot be dialed us.

Speaker 3: It is an excellent drug in auto immune diseases. So one of the hospitals here, and I was slightly involved, not the major involvement. One of the hospitals here tried it. They gave patients that were undergoing bone marrow replacement. They gave high doses of cannabidiol and uh, they saw outstanding results. Uh, many of the patients did not develop the disease. Uh, if they compared to the hundred patients that they had previously and they sold it, there is a, a 50 percent improvement or it was both in the simple cases, relatively simple cases. And both in the very serious cases, it went down by 50 percent now dead. Repeating that on a very large scale, very. I think they have now several hundred patients and I understand that it's working very well and they took a patent and accompanies trying to develop kind of be dial as a drug.

Speaker 3: In this particular case, and I sincerely hope that it will work exactly. Now this is the positive thing, but there are many other autoimmune diseases like diabetes type one children, which the body attacks the cells that produce insulin and the kid doesn't have enough insulin in his sick, very sick sometime. Well, we showed that in mice in a very good model of mice. It works, kind of be dialed. Definitely works. We published that six, seven years ago. Now we try to push a clinical trial. I mean, after all, I'm a, uh, an academic. I kid, I don't have night at the. I have neither the budgets, no. Uh, um, the administrative, uh, ability to, to, to do a clinical trial. And I've been unable to do it, are quite a few others that many out immune diseases. So why shouldn't we go and try to go head?

Speaker 3: We cannot be dial pure cannabidiol in autoimmune disease in Germany. There was some trial in schizophrenic schizophrenia is not an autoimmune disease, but we had shown together with the uh, south Americans in a single case of a young girl, a woman that had a very serious schizophrenia disease. We gave her kind of be dialed in years ago and while she was getting the canopy down, she was in a good shape. So the Germans tried that on a large number of patients and they did it very thoroughly and the results were excellent. They compared cannot be dialed two, one of the drugs that's being used in schizophrenia, a good drug, but it causes side effects and many of the patients and not happy with the side effects in this case can be dialed, worked as, uh, as well as the known drug. But it didn't, it causes no side effects.

Speaker 3: So that was three years ago, haven't heard that anybody's continuing with that cannot be dial is not considered the 90 schizophrenia drug today. Why? I mean, we have proof that it is essentially is what you're saying. We showed in one kid the Germans had done a lot of the patients works. Okay, fine. Yeah. Lots of things that they have to be eh shown, for example, it works. Now does it work, uh, for a long period of time? I say you don't know. Right? But we've done that. Right? And you cannot do that in mice. One has to do that in humans to continue the administration. Two years, we know that thc, the psychoactive compound it causes stoller and one has to give higher doses. Sold the time. We don't know whether that's true for cannot be Donald, right? Maybe it is, maybe it isn't, but we have to keep going and uh, lots of things to be evaluated.

Speaker 4: Let, let's, let's, uh, uh, make sure that, that we, we cover the, you know, we're talking about human beings here, right? And we're talking about the way that the human body interacts with cannabidiol and a thc. That endocannabinoid system is something that is the most fascinating thing to me as far as cannabis. It's all fascinating, but the fact that my body is built for cannabis and cannabis is built for my body is remarkable.

Speaker 5: Yeah.

Speaker 3: Can you take us through how this actually works? Well, you see, when we identified the thc is the psychoactive compound, people started working in our group and many of the groups, and I'm happy to say to the excellent groups in the field, we learned a lot about the chemistry, the biochemistry, pharmacology, what it does in the body. Everything was fine and there was a lot of work that was done over the next 20 years. One thing that we didn't know at that time, how the hell does it work? What's the mechanism? There had been some wrong suggestions in the literature that it's nonspecific. Whatever non specific means. And uh, there is no specific mechanism. Well, we showed Bam it chemical by chemical means that is not correct. And a group in. I'm in St Louis and in holiday, a young researcher that time, uh, she found together.

Speaker 3: We tell a student, build a vein, they founded, there is a receptor that was in the eighties, mid eighties. Well, receptor is something that is in the body and is being stimulated though suppressed by compound that we make at times that compounds from the plant or synthetic ones that the act on the same. Just by chance, no, no real reason. I mean there is no reason why the cannabis plant will be interested in stimulating a receptor in our body. I can't see the deployment can say, well, I want to stimulate the receptor in a human being. They couldn't care less Isu, right? Anyway, the plants, the plant, right? So I thought, well, if we have a receptor, obviously exists because there are compounds that we produced the animals producing and let's look for them. And uh, uh, build. The vendor at that time had come over as a postdoc student, wanted to learn some chemistry and I thought, well, let's do that kind of chemistry.

Speaker 3: So we started extracting, porque eh brains peer rains here in Israel, here in Israel. Now pigs biochemically are closely related to humans. I hope the pigs are not offended, but what we've done with the place, right? So we used to go to Tel Aviv where they had a, meet a places that had a pig brains and my big brains bring them to Jerusalem and extract them and welcome them. And so we worked for nearly two years on that. And ultimately we isolated the small amount of a material, uh, which we call the Nanda might, which stimulates a, that particular receptor. We synthesize it then yes, it's essentially as active as thc, except that in the body it's broken down very fast. THC is not broken down in the body very fast, but otherwise they are, uh, do the same. So chemically they're completely different except that in both cases, both thc and the Nanda might do now dissolve in water.

Speaker 3: They dissolve only in liquids in the body. So in this respect, a physical away, if you wish. In this respect, they are closely related, the structurally completely different. So as far as my body is making an atomized, which is essentially a similar, as you're saying to Thc, how is that possible? Well, the body has nothing to do with the cannabis thing there. There is a receptor them quite a few receptors for other molecules. Very important, extremely important in the physiology. There is a compound called dopamine. Now when Mr. Dopamine is in a, there is a lot of it than a in a certain places of the brain. Then the person is schizophrenic, right when he doesn't have enough dopamine in other places of the brain. Uh, he may have Parkinson's, so it receptors have to be well regulated, the body has to weld, regulate, receptive, so dopamine is one of them.

Speaker 3: Saratonin is another one, and then quite a few receptors, not too many, but there are quite a few receptive and all of them have their own, a neurotransmitter. They had their own receptors and these compounds of the receptors and the body has to regulate them. Uh, and this is how we get to, uh, uh, basically, uh, a deficiency as far as happens, right? It can happen. There is a deficiency. Now, eh, surprisingly, the endocannabinoid receptor was never discovered, right? A dopamine Serotonin, we're known in the thirties, forties, a, the endocannabinoid system became known in the nineties with the endocannabinoid receptors. There are two of them. One that Alan Khalid discovered. Another one who discovered the in the, in England, CB one, CB two, yeah. Strangely enough, the endocannabinoid system, which is not much more complicated than the dopamine. The serotonin, many other systems was not discovered previously.

Speaker 3: Strange. But that, that's it. So we had the receptors, we discovered the Nanda might and the second neurotransmitter, few years later called to age that to age is a long name, but now people always use it to agents. So we have two compounds that are more or less doing the same thing, more or less. There's slight differences. And these compounds the receptors, the enzymes that synthesize these compounds, the enzymes that break down these compounds old. This is the system, the endocannabinoid system. And they have been thousands and thousands of papers on this system since our paper on an under bite has been cited almost 4,000 times, right? We identified another might a few years later where I identified to age these compounds are of major importance in the body. They are involved in regulation and they have activities of their own, uh, surprisingly. And then the might has never been administered as such to a human patient or human being, which is strange and a little bit silly because when insulin was discovered in the twenties, again, active compound that our body produces and it has a lot to do with regulation

Speaker 2: of a sugar levels and so on, and it's an outstanding drug, has been an outstanding drug for 60, 70 years. It became a drug six months after it was discovered. It was given to patients shortly after it was discovered. The same is true with penicillin. When penicillin was identified by a group in Oxford within weeks, they started giving it to patients and, uh, it developed to be a major drug during the Second World War. Saved millions of, of wounded soldiers. Yes, Amanda might, although it was discovered 20 years ago, has never, never been administered to a human being or human patient. Why not? To this day? It's not toxic. It does not cause any side effects. Never.

Speaker 4: Yeah. So you, you, I asked you a why and you say why? And you said, you know, it has to do with the legality. I'm sure along the way here, you must have thought about, you know, what, what has happened as far as the legal construct, uh, in relation to cannabis, W, w, w when you think about that, well, what do you think actually has happened? I see all of these books that, uh, have a, you know, marijuana, marijuana, 80 for marijuana, reconsidering marijuana, marijuana, reconsidered

Speaker 2: w.

Speaker 4: What do you think has happened politically and legally and what, what are, what's your take on that side of this, you know, the non science of it.

Speaker 2: Well, as you know, Mary became an illegal drug many quite a few decades ago, roughly 80 years and even though people didn't know much about it, but a soda did, causes, effects of this type or another type in it was, became illegal drug and uh, becoming an illegal drug. That meant that everything that comes from cannabis is illegal, so cannot be dial happens to be present in this particular plant has nothing to do with the medical activity, but legally it came from the same plant in them for a, it's under illegal side. So, uh, now in many places people are trying to change it, just spoke to the Ministry of Health and the me. Look, we'll still keep it there, you know, to, to be sure what's going on. But, uh, in your case, doing research will easily give you a permit to continue work because we know that is not, uh, anything that, uh, has, uh, and can be used illegally.

Speaker 2: So things are moving, things are changing, but, uh, but that changing slowly at different places, different times in the US, as I said, it's still cannot be dial a is still in the same level of uh, um, the illegality is heroin, which is kind of ridiculous. Right? So you, you think it's ridiculous to do you think beyond that is what I'm saying. Um, you know, in, uh, in the u s it was made illegal. There's, you know, uh, if you go back and you read, it's maybe because of the duponts and it's, you know, maybe because of the Morgan send a, it's maybe because of the hearsts, uh, that, uh, had business interests that were threatened by hemp and cannabis. And, uh, you've talked about the jazz musicians and we talked about the farmers and why do you think about that type of stuff or do you want to think about the details?

Speaker 2: I quite frankly, I doubt it because, um, it was a minor. It was not. The drug at that time in the thirties was in pharmacies. It was not a, I don't think that the big companies, uh, had much to do with it. Maybe what happened was that in the early thirties, alcohol was still illegal in the states and they had a big, they had a lot of people working in a, in whatever government office was involved, all of a sudden are in the, I think it was 1933 alcohol became legal. So there were a lot of people that, uh, were out of a job. So I've been in possibly positively without having any data possibly they thought, well, let's move from alcohol to marijuana or other drugs. And that's what happened rather than the big companies, the big companies. Uh, I don't think that there, there were very much involved that was not much of a competition.

Speaker 2: Interesting. So Harry Anslinger, who was running a prohibition of alcohol, did actually move that infrastructure over to really, I'm not a, I don't know the, I'm just thinking that it is a possibility, but I gotcha. So, so then let's get back to the medicine. You mentioned the fact that Israel now is coming along and it is, you know, it's right here right now. Uh, and, and I love the fact that you've been researching this since the sixties and you still think it's going slowly even though it's happening so quickly at this, uh, at this moment. Right. Why do you think it's a slow, even though it's moving quickly? Well, their aspect is that moving very well ahead. For example, within the medical school medical, uh, you need that we have at the university medical faculty, uh, we established a center for cannabinoid research and we have 20 groups that actually work on cannabinoids, endogenous cannabinoids, different different groups work in chemistry, pharmacology in the clinic and there is a lot of talk and we're going ahead with all these things.

Speaker 2: So he made, there are many other groups at other universities that are doing this. May Be because there was a basis for cannabis research and maybe it started with our group. Pathetic Standard started with your group is that it expanded fast later. So there are a lot of people working in and so we are expanding. We're going ahead. Uh, the problem with human trials is a major problem. Yes, it's difficult to do. It's expensive. And so there are a few groups doing clinical trials in this country. Yeah, we started the clinical trial in cancer. Uh, but uh, it's going slowly. I don't, we don't have the financial backing for that now, but going back to cancer and cannabis, Eh, it is. Thousands of people throughout the world are using cannabis for cancer. Indeed, a cancer is not one disease. There are so many types of cancers.

Speaker 2: Lung cancer is not the same as another one. There one, a skin cancer does not necessarily have to be the same as a, some kinds of brain cancers. So there are a lots of cancer so that people are treating with cannabis, but there isn't a single, a single clinical trial and any cancer with cannabis cannabinoids, whether it's an extract or it's a pure thc cbd, nothing. There isn't a single. Now that's a shame that should have been solved many years ago. I mean, one should see what is a, what can be done because there are positive results and people are using results that are not clinical result. They're just results. Uh, uh, the anecdotal, that neighbor is using it for his cancer and maybe it will be good for my cancer. Now that's not the way to do it. That's 18th century. A medicine that there should be clinical trials, major clinical trials done by physicians with the exact materials, a reproducible with good statistics and so on.

Speaker 2: But there isn't a single clinical trial published. Maybe a few are going on now, but not a single one that has been published now. That's not the way to do it. Yeah. Do you feel that, you said there may be some that are getting closer maybe to some that are going ongoing right now. What I'm getting from you is that not enough is happening, uh, and it should have happened years and years and years and years ago and it all has to happen right now for it even to be soon enough type of thing. Well, yes, in particular the clinical side and the clinicians that there are that are aware of that and, but it is not simple to do it in the, in the US. I'm not aware of any major clinical trials going on now at the moment. Maybe that small ones, but nothing major that, that your change. What can we do to help change that?

Speaker 2: Have you? Well, I assume that, uh, a financial piece or universities or even the government should push forward from. And if they say we want a clinical trial, well the FDA has a little bit of money. I think they have a budget of 30 billion. Well we'll see. But so far, yeah. Well maybe that will be cut down. I don't know. But I assume that they can initiate good clinical trials, uh, companies, uh, smoke complicated because there is no pattern there and the company wouldn't like to spend a, a many, many millions of dollars to develop a, to, to do a clinical trial. But maybe it can be done. I think, for example, the Kenner be dial trial is being done. There is no pattern there because we had already published. A chances are that they will get an exclusivity, say, well, because you're spending so much money, we'll give you exclusivity in this particular field for five or six years.

Speaker 2: This was done with thc 15 years ago. Right? So it can be done with kind of be dialed, let's say, or even with the or even with the mixture. We're not sure what's the best. Maybe the best thing is a 20 to one CBD thc. Maybe Navy could do something else, but we don't know. I mean these things should be studies, studied, evaluated statistics should be there. Uh, but at the moment there is nothing. That's not the way to do it. That's not the way to do it. But as we get closer, you know, and again, I, I hear your frustration and I see your frustration, but you did mention a, there is now a community, um, and uh, the community,

Speaker 4: uh, you say maybe it started with us and I said, I don't know if you heard me, it definitely started with you and your group. Uh, so when I sit across from you. Yeah. Uh, I see Isaac Newton, I see Galileo, I see Mary Curie, I see, I see Copernicus for water away, but it doesn't matter. It's a little bit far away. But you, you realize the import of the work that you have done. Yes. Or, or, or no.

Speaker 2: Well, I believed that it, parts of it were important. Yes. And there are many other things that can be done and are being done. Uh, and I'm happy that many groups are involved and we have been lucky to a large extent that um, so many outstanding groups are collaborating. And uh, for example, we are writing in our paper and um, uh, one of the aspects, and we have full groups and Italian group to American groups, US, Canadian group. And our group working in writing a paper together, 15 orthos, more or less a pretty complicated thing, but we've known each other, we're good friends and we can go and do things together, which is extremely important. And this has happened now. This has been going on for about 20 years and that's one of the ways the whole field is going ahead because of the extra old record, the collaboration between the various groups. So there we are. Do you see the clinical part is neglected partially because of legal problems? Yeah.

Speaker 4: Do you think that we are closer? I understand that you're frustrated that we're not there. Do you think that we're closer in other words? Uh, since we're in 2017, if you can believe it. We're talking about 1963 before and before that, right. We didn't even get into your father and the whole story, but maybe we'll talk again, I hope. Um, do you feel that it may be close now? Well, easiest closer in.

Speaker 2: I know that the new Israel, these there five or six clinical trials going on, right? Yeah. Uh, once they approved clinical trials in the US that we made many, many, many more obviously, right? Yeah. And uh, so once we have the clinical trials will know what's going on in cancer field. Maybe for cancer, a one needs this for cancer, be one. The one needs something else. Maybe the amounts needed a high for one law for the, we don't know. I mean, we're not mice in mice. We know what's on more days, but we're not mice and it has to be developed. It has to be understood was going on inpatients in human patients. That's. This will happen within the next few years. Something else that is going to happen probably is some, you see, when insulin, when antibiotics were discovered, penicillin for example, it was used as penicillin, but today you cannot go and buy penicillin as a drug.

Speaker 2: It doesn't exist as a drug because companies have made the derivatives that are better. After all that a fungus that produces fenestrating doesn't make it for us. It makes it for its own uses. We may need a slightly different penicillin and this is what's happening. If you go, uh, you will, you can buy a derivative of penicillin. The same is true for cortisone. An important hormone that we have when it was discovered was to, it is antiinflammatory. It's great, but in the meantime, a, the companies have developed the derivatives of cortisone. It's a small market, 6 billion, $10,000,000,000, something like that. Yeah. Have quoted quotes but not cortisone. Cortisone you cannot buy, right? So chances are this is will happen with the cannabinoids, maybe cannot be dial. It may continue to be a drug as an extract because people will like to use the cannabis extract and will go on for a pretty long period of time, but chances are that companies will take, cannot be dialed, make derivatives, and have a better drug.

Speaker 2: It's a matter of fact. We have already done something of this sort where they can kind of be dialed, put on a fluorine atom on canopy dial. We even published that and this compound is a little bit better. We're investigating is better than cannot be dial itself. What are you calling it? We don't have a name for that. The name will come, right? No, no, we have, we call it h U Huc, Hebrew University h u f one. Oh, okay. So this particular compound is a, a is better than a, a cannot be dialed itself in some of the things that it's doing in anxiety. For example, when you say it's better, what does that mean? Well, when a nice lower amounts can be dial, unfortunately one has to use very high amounts into schizophrenia trial. I was telling you before people use the 800 milligrams of CBD, which is a lot.

Speaker 2: That's a lot. So, uh, if we can use much less, that's much better. Normally, not necessarily, but no money. So here we have compounds that had to a large extent bit and so we should have under market, I believe both the extract of the plant extracts, but also the derivatives of particular compounds. And uh, people, for example, hit publish academy general compounded. We isolate because CBG, right? Yes. Yeah. M CBGS anti cancer in mice. Maybe by making small changes in the molecule we can enhance the activity in however, cannot be g like compound, which is very active. And there is another field, Amanda might stricture of anonymized, it's a fatty acids bound to amino acid, but then lots of fatty acids bound to amino acids in the body, but 120 of them and nobody looked at them. But these are like an undermined. So the body has a huge number of Amanda might like compounds and this is probably the most interesting, most important a part of cannabinoid research today because these compounds seem to be active, not passive.

Speaker 2: They are active, they have them. One of them we found quite a few years ago works against osteoporosis and it came from a different type of research. It was known that women in the Mediterranean region have less cancer than less osteoporosis than women in the north. And so we thought, let's look at it, but nothing to do with cannabinoids, right? I'm a natural products chemistry. I was interested in natural product, right? So we looked at olive oil, didn't do much, that may be some metabolite. So we made a Metabo a few metabolites of, of what's present in olive oil or lake acid. And one of them turned out to be indeed a very potent anti osteoporotic agent. So it has nothing. The structure is related to anonymize suits. It's an end to my light combo. Another one that we found is a investor constriction and brain injury works in brain injury. Uh, two or three of them actually do that. And so we have about 120 compounds there that seem to be active. And then they are enendomide like comp. One of the things that is fascinating to me is the number of different, um, you call them indications here. We call them qualifying conditions, you know, we call them conditions, you call them indications. How is it possible that this one plant, which is a connected to an animated, you know, in an atomized, is connected to how is it possible that there are so many things

Speaker 3: that can be solved by a derivatives of cannabis. The, at least two reasons. First of all, DHC binds to an important receptor like an enemy, right? So anything that has to do with this receptor thc, somebody involved in this way or that way, can it be double? Is a stranger thing because it, it's a binding to the receptor is minor, but it extra several mechanisms. So there we are, we have two completely different compounds that act through different mechanisms and that's it. So me not being a scientist, I don't quite understand that answer. Well, we don't understand it. I can go a little bit in more detail. Um, cannot be. Dial activates quite a long list of ame receptors in the body. Okay. A one, I'm one going into scientific detail. The different receptors today do different things now they're not so many compounds attacked and so many different receptors.

Speaker 3: And so it happens. There is always a first time and the first time for everything. Yeah. So we, the works by acting in these receptors, it works on different diseases because these receptors that are found in the body, all of them are involved in physiological changes that are going on in our body in. And then if you affect these, um, eh receptors, then chances are that you'll do something now. There is something of major, major importance if he turns out to be correct. And this is a an Italian group, Eh, professor, macaroni of Rome, found, found that cannabidiol in a particular skin disease, it acts not done the symptoms of the disease, but the x and the DNA that is related to that disease. Now you see many of the diseases we have is because of DNA of ours, makes too much of a compound through various routes, but basically the one that started the initial initiates the process. So if it works overtime and you have a compound that regulate the DNA activity, then you're working on the basis of a disease, not the symptoms of the disease and cannot be dialed. They found they didn't in particular skin disease, acts under DNA.

Speaker 2: It logs of DNA, it's called methylation in blogs, the particular dna that's working overtime, and this is the way it, eh, regulate, regulate that disease or helps with that disease, not treat the symptoms, not true anything else through the basis. Now, if this stands out to be true for the many diseases that cannot be dialed work. So then we have something very important here. We have a compound that regulates things in the body by acting on the DNA on the basis. Well, if that turns out, as I said to be true, then we have a major, major, a different way of treating diseases.

Speaker 2: I'm, I want to leave it there, right? Because that is a little bit complicated, scientifically complicated, but, but, uh, and when will we get the next kind of update from them, do you think? Well, they're working on, it's a very complicated situation because he doesn't work directly in the DNA works on something that affects the very complicated, right? But, uh, yes, uh, other people also getting interested in DNA is important DNA of these in disease states. So chances are that we'll see that in the next few years by many groups are very important. So we're going straight to the DNA, which is remarkable. Yeah. So if we can affect, uh, the changes in the DNA that causes certain disease and we don't always know that many times the disease is not caused by you by a single DNA, but by many, many, many genes that are involved in the DNAS and so on. So, but in cases where you have a single thing, then maybe just, maybe that's what's going on.

Speaker 4: It is a, it is so fascinating. It is amazing to talk to you. Um, I have three final questions that I'm going to ask you. I'll tell you what they are and then I'll ask you them in order. Um, you know, uh, the first one is what has most surprised you in cannabis? The second is what has most surprised you in life? And then I asked a soundtrack song. So on the soundtrack of Rafi michelins life, what is one track? One song that's got to be on there, but that's last. I, I cannot wait for your answer to what has most surprised you in cannabis?

Speaker 4: CAA cannot be dial as a drug that affects so many diseases that this really surprised me. The fact that the CEO's effect diseases is fine. One good thing. Well, it, it causes a lot of perfect. But I was really surprised by cannabidiol. It's a surprising compound. Nobody was really interested in it. Our first paper actually was uncannily dial, not on the right. And uh, Eh, it is unexpected really. That one compound would do so many things and there was no reason to believe that cannot be die. Will do that. It makes a, are you saying basically scientifically it, it does not make sense that it is so effective?

Speaker 2: Well, it's surprising now that we know, but it doesn't make sense. I gotcha. But, um, you know, you'll get surprises all the time in science. One is delighted to, to have a surprise to see something sometimes one thinks about it and I'm happy that that happens, uh, out of 10 times if they have an idea. Nine don't work in one works. Right. Okay.

Speaker 4: There you go. Just quickly, you know, as far as you approaching cannabis, um, out of, uh, out of everything I know that you in the, in the past I've heard you, uh, mentioned the fact that, you know, some of it has to do with the fact that I didn't have too much of a budget. Right?

Speaker 2: Well, I never had much of a budget, uh, at the beginning we had no budget, don't right. And uh, but once n a so that, well, we are one of the first groups working in that and they were interested in knowing what's going on. I had a research budget, not a major research budget, about $100,000 a year under $20,000 a year from Nih, which is quite unusual because nih normally doesn't give them any abroad, rightly so. And uh, and I got, had the research budget from Nih for about 40 years. So in this respect, um, I was really happy to work with them and I have to say, did they never, never interfered with what I was doing. I had to apply every three years. They would say yes and no, and I had to make the corrections and so on or changes if you wish of the, of what I said I'm going to do.

Speaker 2: But once I had the budget I was, they never interfered with anything. They didn't say you should look for the bad effects and not for the good effects. Nothing of that sort. Uh, as a metro effect, I knew most of the directors of the National Institute of Drug Abuse. We used to get a bunch of regional, a national institute of Mental Health, I believe. And then it moved to the National Institute of Drug Abuse. I've known most of the directors there. Most of them were outstanding scientists. The person in charge, a head of the National Institute of Drug Abuse. She's an outstanding scientists, really good. And she still works in science. She still has her labs, I think nothing, nothing in the National Institute of Drug Abuse Within another institute. So they won't be any interference or conflicts. And she does that and she's a good scientist, have known them. They're outstanding. And in this respect I just, Eh, I'm amazed s how things worked positively in the states in certain fields.

Speaker 2: I am not interested in politics, but in this case that's outstanding. The person that's in charge of neither, she was not an administrator before. She was doing some good work. So excellent research. She's not even American. She's Mexican and uh, uh, they thought, well, she's a good administrator. She knows a lot about the field, she seems to be okay and they appointed head of neither with a huge budget night. She's been there now for the last six, seven years and that's it now, even though she's not American and she studied in Mexico and worked in Mexico. She's kind of a kind of a Mexican because she's basically European. She's, I think, the granddaughter of Trotsky. Really? Yeah. No, yes. Out of everybody. Trotsky. That's a. well, what does that make you think? Well, it makes me think that the US knows how to deal with excellent people.

Speaker 2: She's an excellent scientist. They appointed. Yeah. How background. Well, it's an. It's interesting to talk about. It has, it has nothing to do with, with the way she's running things. There you go. There you go. And I've seen that with quite a few people. I mean, in the US, you see many first generation, uh, people, scientists, physicians, outstanding. They opened the doors. It's possible to do it. Not In many countries. You can do that right now, may in most countries, you have to have a background of this are not in the US, in the US first generation scientists. Uh, you can see that in a development of nuclear, nuclear energy. Most of the people who are first generation Americans, if at all the joe goes to Athena, one had to know Hungarian old German and English was a optional now. Right? And, and they know how to attract people and give them their facilities. So this is something that most Americans don't realize that we have. Yes.

Speaker 4: Yeah. Are you, you mentioned, uh, uh, I mentioned a few scientists earlier, you mentioned a German or Hungarian science scientists who were your, um, you know, uh, not necessarily mentors, but who, what scientists did you see

Speaker 2: study and really get a kind of, uh, uh, inspired by, well, as a natural product chemist. I worked with a professor zoned high who was German born, but that studied, he was an English and a British citizen, I think had worked at Harvard for many years. Then he was involved in Mexico in developing, uh, some extremely interesting and important drugs. And became very rich out of that. Then he came to Israel and he was head of the Department of Organic Chemistry and I did my phd with him and I learned quite a bit, although I moved to a different fields later on. Another person who died recently was called Djerassi. I don't know whether you've heard of him. I'm not as familiar now. Well, ecology Rossy, uh, came to the US when he was 17, 18 or something like that,

Speaker 5: uh,

Speaker 2: became a extremely well known chemist. He was also involved with that group in Mexico. There they developed the first, uh, antipathy let pill and it's being used by many millions. Sure. And, uh, he became very, very rich, had one of the major collections of art in the US and um, he happens to be a cousin of mine, but that had nothing to do with it. He was later professor at Stanford and he was one of the major people in the field of natural products. I see. So, uh, and we were closely related than mean scientifically and so on. What about outside of natural, uh, you know, well, just premier thinkers in your, in your mind, in the fields of fire, in the fields of science. And there was a professor, Bill Peyton, it outward university in the UK. He was a pharmacologist. We wrote the book together and he was a fantastic pharmacology.

Speaker 2: He got a knighthood and so he became Sir William Peyton and um, passed away a few years ago. So the cultural scene last year and a years, they weren't people that influenced my work to a certain extent. So jumping off of that, uh, what has most surprised you in life if you've been around for a few years at least? Right. Well, let's move to something else. The thing that surprises me now. Okay. Uh, the Thai remained alive in Europe during the Holocaust. So let's, I was a, yeah, a young fellow then 10 years old. Your father went to a concentration camp. Survivor was in a concentration camp in Bulgaria, but, uh, due to many different factors, uh, the Jews in Bulgaria were not sent to Auschwitz. And although there, there were a lot of laws against the Jews. And so on, very difficult times, uh, but you know, there is a difference between remaining alive or being burned in Auschwitz.

Speaker 2: And so, uh, still surprises me that that's what happened because it didn't happen in most other countries in Europe. Uh, the reason for that. There are lots of reasons because originally the Bulgarians sent out 10,000 Jews to Auschwitz, Jews that were, eh, not in the old Bulgarian territory, but there were in territories that were given to the Bulgarians from the GE by the Germans. They were associated with the Germans and the Germans when they conquered the Yugoslavia and Greece and so on, gave part of the adult those lands to the Bulgarian. And the Jews that lived in those parts was sent early in the game. Nineteen 42, I believe, to Auschwitz. And essentially all of them were killed.

Speaker 2: But a year later the Jews was supposed to be sent to Auschwitz and we will not send for several reasons. One of them was a people in the parliament learned that this is going to happen. And the vice chairman of the Bulgarian parliament, uh, wrote a letter that about 40 other members of the parliament signed to the Kink, was mostly a dictator, a saying that it is against the law. The law does not allow Bulgarian citizens to be sent abroad against their will or something of that sort. And probably the most important thing was that the king being a dictator, he could do a lot of things. And this was 19, 40, early 19, 43. Now Ella Maine was late 19, 42. Stalingrad was the end of 42. So maybe the king thought, well this will not sound very well after the war if the Germans don't win the war, if I send 50,000 Jews to go to Poland to be killed or whatever.

Speaker 2: So I think this is the main reason now maybe that's one of the reasons why when the king went to see Hitler on the way back, he died on the plane. It's a, somebody told me or it is considered that he was given instead of an oxygen mask and nitrogen mask and he died in the plate. Maybe one. This was one of the reasons because the Nazis were not happy with what's, what was going on, right. They'll all kinds of stories behind it. So I think that I'm still surprised that I remained a life. That's all.

Speaker 4: Uh, there's, there's no way for me to, uh, follow that in any way other than to say we're, we're, uh, I, and we are very pleased that you're here no matter what. Middle Cbo. Cool. Yeah. We, uh, so now on a soundtrack so that we end on a lighter note, Raffy, what is one song maybe that, uh, that you think about, that you enjoy, that, uh, should be, that should be with you and with us? Yes.

Speaker 2: Well, probably the songs in my fair lady. A really? Yes. I really like it. It's um, I wouldn't say academic, but it's a kind of teaching somebody and the getting involved, somebody in pushing somebody up and done in such a very, very pleasant way. That's one thing. And the other one is a lighter one. Silly one if you wish you the barber of Seville. Oh, perfect. Figueiredo Barbra Seville. When I was in Spain and we were in Seville, this is my favorite opera by the way. I was looking for a barber to get a shot down, say, look, this is the Barbara Smith, but I didn't find what you literally looked for a barber of Seville and could not find one these. Of course, I like music. I really like music and Mozart, Chopin. Uh, I'm old. The other classical ones, I'm not so sure that I like that very modern music now if I like very much and uh, so on. But the music that's been composed today, I just don't understand. Maybe in 50 years time people will, but I certainly liked music and listened. As far as yours, your work is much, maybe the same bright. Maybe in 50 years everybody will understand, but we in the cannabis industry to understand. Thank you so much for your work, for your time, sir. And there you have the copernicus of cannabis.

Speaker 1: What an honor. What a pleasure, what an experience. Talking to a rafter, Michelle, um, who has been in this industry longer than you, no matter who you are. So I can't think of enough. First Time. Hope you enjoyed it too. I know you did. Stay tuned.

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